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MHC matching improves engraftment of iPSC-derived neurons in non-human primates.

ABSTRACT: The banking of human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cells (iPSCs) is considered a future clinical strategy for HLA-matched cell transplantation to reduce immunological graft rejection. Here we show the efficacy of major histocompatibility complex (MHC)-matched allogeneic neural cell grafting in the brain, which is considered a less immune-responsive tissue, using iPSCs derived from an MHC homozygous cynomolgus macaque. Positron emission tomography imaging reveals neuroinflammation associated with an immune response against MHC-mismatched grafted cells. Immunohistological analyses reveal that MHC-matching reduces the immune response by suppressing the accumulation of microglia (Iba-1+) and lymphocytes (CD45+) into the grafts. Consequently, MHC-matching increases the survival of grafted dopamine neurons (tyrosine hydroxylase: TH+). The effect of an immunosuppressant, Tacrolimus, is also confirmed in the same experimental setting. Our results demonstrate the rationale for MHC-matching in neural cell grafting to the brain and its feasibility in a clinical setting.Major histocompatibility complex (MHC) matching improves graft survival rates after organ transplantation. Here the authors show that in macaques, MHC-matched iPSC-derived neurons provide better engraftment in the brain, with a lower immune response and higher survival of the transplanted neurons.

SUBMITTER: Morizane A

PROVIDER: S-EPMC5577234 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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MHC matching improves engraftment of iPSC-derived neurons in non-human primates.

Morizane Asuka A Kikuchi Tetsuhiro T Hayashi Takuya T Mizuma Hiroshi H Takara Sayuki S Doi Hisashi H Mawatari Aya A Glasser Matthew F MF Shiina Takashi T Ishigaki Hirohito H Itoh Yasushi Y Okita Keisuke K Yamasaki Emi E Doi Daisuke D Onoe Hirotaka H Ogasawara Kazumasa K Yamanaka Shinya S Takahashi Jun J

Nature communications 20170830 1

The banking of human leukocyte antigen (HLA)-homozygous-induced pluripotent stem cells (iPSCs) is considered a future clinical strategy for HLA-matched cell transplantation to reduce immunological graft rejection. Here we show the efficacy of major histocompatibility complex (MHC)-matched allogeneic neural cell grafting in the brain, which is considered a less immune-responsive tissue, using iPSCs derived from an MHC homozygous cynomolgus macaque. Positron emission tomography imaging reveals neu ...[more]

PMID: 28855509

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Project description:Our understanding of the molecular processes underlying Alzheimer's disease (AD) is still limited, hindering the development of effective treatments, and highlighting the need for human-specific models. Advances in identifying components of the amyloid cascade are progressing, including the role of the protein clusterin in mediating ?-amyloid (A?) toxicity. Mutations in the clusterin gene (CLU), a major genetic AD risk factor, are known to have important roles in A? processing. Here we investigate how CLU mediates A?-driven neurodegeneration in human induced pluripotent stem cell (iPSC)-derived neurons. We generated a novel CLU-knockout iPSC line by CRISPR/Cas9-mediated gene editing to investigate A?-mediated neurodegeneration in cortical neurons differentiated from wild type and CLU knockout iPSCs. We measured response to A? using an imaging assay and measured changes in gene expression using qPCR and RNA sequencing. In wild type neurons imaging indicated that neuronal processes degenerate following treatment with A?25-35 peptides and A?1-42 oligomers, in a dose dependent manner, and that intracellular levels of clusterin are increased following A? treatment. However, in CLU knockout neurons A? exposure did not affect neurite length, suggesting that clusterin is an important component of the amyloid cascade. Transcriptomic data were analyzed to elucidate the pathways responsible for the altered response to A? in neurons with the CLU deletion. Four of the five genes previously identified as downstream to A? and Dickkopf-1 (DKK1) proteins in an A?-driven neurotoxic pathway in rodent cells were also dysregulated in human neurons with the CLU deletion. AD and lysosome pathways were the most significantly dysregulated pathways in the CLU knockout neurons, and pathways relating to cytoskeletal processes were most dysregulated in A? treated neurons. The absence of neurodegeneration in the CLU knockout neurons in response to A? compared to the wild type neurons supports the role of clusterin in A?-mediated AD pathogenesis.

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MHC matching improves engraftment of iPSC-derived neurons in non-human primates.

Publications

MHC matching improves engraftment of iPSC-derived neurons in non-human primates.

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